Esophageal Microbiome, Epithelial Gene Expression, and Response to Topical Swallowed Steroids in Pediatric Eosinophilic Esophagitis

小儿嗜酸粒细胞性食管炎的食管微生物群、上皮基因表达以及对局部吞咽类固醇的反应

• 批准号: 10432560
• 负责人: Girish Hiremath
• 金额: $ 25.95万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10432560
• 关键词: Acinetobacter; Address; Allergens; Biopsy; Biopsy Specimen; Child; Childhood; Classification; Clinical; Collagen; Control Groups; Cytokine Signaling; Deglutition; Disease remission; Distal; Distress; Down-Regulation; Ecology; Endoscopy; Environmental Risk Factor; Eosinophilic Esophagitis; Epithelial; Esophageal Stenosis; Esophageal Tissue; Esophagus; Extracellular Matrix; Failure to Thrive; Fibrosis; Food; Foundations; Functional disorder; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; High Prevalence; Histologic; Homeostasis; Impairment; Incidence; Inflammatory Response; Knowledge; Lead; Longitudinal Studies; Mediating; Molecular; Mucous Membrane; Operative Surgical Procedures; Outcome; Outcome Study; Pathologic; Pathway interactions; Patients; Pediatric cohort; Peptide Hydrolases; Play; Prevalence; Property; Protocols documentation; Quality of life; Research; Role; Sampling; Steroid therapy; Steroids; Structure; Symptoms; Testing; Time; Tissue Sample; Treatment Efficacy; Up-Regulation; Vomiting; bacterial community; base; cohort; disabling symptom; eosinophil; eosinophilic inflammation; feeding; high risk; host microbiome; immune function; improved; insight; metagenome; metagenomic sequencing; metatranscriptomics; microbial; microbial community; microbiome; microbiome composition; microbiome signature; microbiota; novel; personalized care; personalized therapeutic; predicting response; response; restoration; therapy outcome; transcriptome; treatment response

Summary Eosinophilic esophagitis (EoE) is an increasingly prevalent allergen-mediated clinico-pathologic condition. It is characterized by the presence of esophageal symptoms and impaired esophageal epithelial barrier in the setting of eosinophilic inflammation. The children with EoE suffer from debilitating symptoms such as vomiting, feeding difficulties, inability to swallow, and failure to thrive. Topical swallowed steroids (TSS) are the mainstay of EoE therapy and can lead to improvement in symptoms, histologic remission, and restoration of the epithelial barrier function. However, over 50% of children with EoE may not respond to TSS and continue to suffer from unremitting symptoms which can negatively impact their quality of life. Additionally, the uncontrolled eosinophilic inflammation can further compromise the esophageal epithelial properties and lead to sub-epithelial fibrosis resulting in esophageal stricture and esophageal food impactions requiring emergent endoscopy or surgical intervention. To date, very little is known about the factors associated with response to TSS in children with EoE. In particular, the role of esophageal microbiome and how it interacts with the esophageal epithelium to impact the response to TSS in children with EoE has not been studied. It is important to understand this relationship as the rapid increase in the incidence and prevalence of EoE strongly indicates that environmental factors such as esophageal microbiome may have an essential role in modulating the treatment response in EoE. The objective of this application is to investigate the role of the esophageal microbiome and its cross-talk with the host epithelium in TSS responders (EoE-TSSr), TSS non-responders (EoE-TSSnr) and non-EoE controls. For the first time, it would determine whether TSS therapy outcomes are derived in part by resident esophagus microbiota structure and function that can potentially alter esophageal barrier integrity and immune function. Using a pediatric cohort of EoE- TSSr, EoE-TSSnr and non-EoE controls we will: a) characterize the microbiome composition and functional capability at the species level in the esophagus tissue samples, b) determine the mechanistic association between active esophagus microbiome, host epithelium expression profiles, and TSS therapy efficacy. The outcomes of this study will expand our understanding about the factors associated with response to TSS in pediatric EoE. In the long term, this study will lay the foundation for personalizing the care in pediatric EoE.

总结